tbuckley/cabot-search huggingface dataset:
Progesterone Administration and Progressive Sleep Apneas
Authors: Kingman P. Strohl
Journal: JAMA (1981)

Nine adult patients with obstructive sleep apnea syndrome were administered medroxyprogesterone acetate, 60 to 120 mg/day, and the effect of medroxyprogesterone on clinical symptoms and obstructive apneas during sleep was assessed. Four patients responded with resolution of daytime sleepiness, disappearance of pedal edema, and a decrease in the number of obstructive apneas during sleep. Cessation of therapy led to a return of daytime sleepiness in three and an increase in obstructive apneas in all four subjects. Two responders experienced side effects of alopecia or decreased libido. Before medroxyprogesterone therapy, responders were distinguished from nonresponders only by the presence of a significantly lower resting arterial oxygen tension during wakefulness. We characterize a subgroup of patients who benefit from medroxyprogesterone therapy by reducing obstructive apneas during sleep. (<i>JAMA</i>1981;245:1230-1232)
Skin Tone Analysis for Representation in Educational Materials (STAR-ED) using machine learning
Authors: Girmaw Abebe Tadesse, Celia Cintas, Kush R. Varshney, Peter Staar, Chinyere Agunwa, Skyler Speakman, Justin Jia, Elizabeth E. Bailey, Ademide Adelekun, Jules B. Lipoff, Ginikanwa Onyekaba, Jenna C. Lester, Veronica Rotemberg, James Zou, Roxana Daneshjou
Journal: npj Digital Medicine (2023)

Abstract Images depicting dark skin tones are significantly underrepresented in the educational materials used to teach primary care physicians and dermatologists to recognize skin diseases. This could contribute to disparities in skin disease diagnosis across different racial groups. Previously, domain experts have manually assessed textbooks to estimate the diversity in skin images. Manual assessment does not scale to many educational materials and introduces human errors. To automate this process, we present the Skin Tone Analysis for Representation in EDucational materials (STAR-ED) framework, which assesses skin tone representation in medical education materials using machine learning. Given a document (e.g., a textbook in .pdf), STAR-ED applies content parsing to extract text, images, and table entities in a structured format. Next, it identifies images containing skin, segments the skin-containing portions of those images, and estimates the skin tone using machine learning. STAR-ED was developed using the Fitzpatrick17k dataset. We then externally tested STAR-ED on four commonly used medical textbooks. Results show strong performance in detecting skin images (0.96 ± 0.02 AUROC and 0.90 ± 0.06 F 1 score) and classifying skin tones (0.87 ± 0.01 AUROC and 0.91 ± 0.00 F 1 score). STAR-ED quantifies the imbalanced representation of skin tones in four medical textbooks: brown and black skin tones (Fitzpatrick V-VI) images constitute only 10.5% of all skin images. We envision this technology as a tool for medical educators, publishers, and practitioners to assess skin tone diversity in their educational materials.
PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer
Authors: Antonino Glaviano, Aaron S. C. Foo, Hiu Y. Lam, Kenneth C. H. Yap, William Jacot, Robert H. Jones, Huiyan Eng, Madhumathy G. Nair, Pooyan Makvandi, Birgit Geoerger, Matthew H. Kulke, Richard D. Baird, Jyothi S. Prabhu, Daniela Carbone, Camilla Pecoraro, Daniel B. L. Teh, Gautam Sethi, Vincenzo Cavalieri, Kevin H. Lin, Nathalie R. Javidi-Sharifi, Eneda Toska, Matthew S. Davids, Jennifer R. Brown, Patrizia Diana, Justin Stebbing, David A. Fruman, Alan P. Kumar
Journal: Molecular Cancer (2023)

Abstract The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.
Combining cardiopulmonary exercise testing with echocardiography: a multiparametric approach to the cardiovascular and cardiopulmonary systems
Authors: Lavinia Del Punta, Nicolò De Biase, Silvia Armenia, Valerio Di Fiore, Davide Maremmani, Luna Gargani, Matteo Mazzola, Marco De Carlo, Alessandro Mengozzi, Tommaso Lomonaco, Gian Giacomo Galeotti, Frank L Dini, Stefano Masi, Nicola Riccardo Pugliese
Journal:  (2023)

Abstract Exercise intolerance is a prominent feature of several cardiovascular conditions. However, the physical effort requires the intertwined adaptation of several factors, namely the cardiovascular system, the lungs, and peripheral muscles. Several abnormalities in each domain may be present in a given patient. Cardiopulmonary exercise testing (CPET) has been used to investigate metabolic and ventilatory alterations responsible for exercise intolerance but does not allow for direct evaluation of cardiovascular function. However, this can readily be obtained by concomitant exercise-stress echocardiography (ESE). The combined CPET-ESE approach allows for precise and thorough phenotyping of the pathophysiologic mechanisms underpinning exercise intolerance. Thus, it can be used to refine the diagnostic workup of patients with dyspnoea of unknown origin, as well as improve risk stratification and potentially guide the therapeutic approach in specific conditions, including left and right heart failure or valvular heart disease. However, given its hitherto sporadic use, both the conceptual and technical aspects of CPET-ESE are often poorly known by the clinician. Improving knowledge in this field could significantly aid in anticipating individual disease trajectories and tailoring treatment strategies accordingly. Therefore, we designed this review to revise the pathophysiologic correlates of exercise intolerance, the practical principles of the combined CPET-ESE examination, and its main applications according to current literature.
Sorting nexin 3 exacerbates doxorubicin-induced cardiomyopathy via regulation of TFRC-dependent ferroptosis
Authors: Wenjing Yu, Yuehuai Hu, Zhiping Liu, Kaiteng Guo, Dinghu Ma, Mingxia Peng, Yuemei Wang, Jing Zhang, Xiaolei Zhang, Panxia Wang, Jiguo Zhang, Peiqing Liu, Jing Lu
Journal: Acta Pharmaceutica Sinica B (2023)

The clinical utilization of doxorubicin (Dox) in various malignancies is restrained by its major adverse effect: irreversible cardiomyopathy. Extensive studies have been done to explore the prevention of Dox cardiomyopathy. Currently, ferroptosis has been shown to participate in the incidence and development of Dox cardiomyopathy. Sorting Nexin 3 (SNX3), the retromer-associated cargo binding protein with important physiological functions, was identified as a potent therapeutic target for cardiac hypertrophy in our previous study. However, few study has shown whether SNX3 plays a critical role in Dox-induced cardiomyopathy. In this study, a decreased level of SNX3 in Dox-induced cardiomyopathy was observed. Cardiac-specific Snx3 knockout (Snx3-cKO) significantly alleviated cardiomyopathy by downregulating Dox-induced ferroptosis significantly. SNX3 was further demonstrated to exacerbate Dox-induced cardiomyopathy via induction of ferroptosis in vivo and in vitro, and cardiac-specific Snx3 transgenic (Snx3-cTg) mice were more susceptible to Dox-induced ferroptosis and cardiomyopathy. Mechanistically, SNX3 facilitated the recycling of transferrin 1 receptor (TFRC) via direct interaction, disrupting iron homeostasis, increasing the accumulation of iron, triggering ferroptosis, and eventually exacerbating Dox-induced cardiomyopathy. Overall, these findings established a direct SNX3–TFRC–ferroptosis positive regulatory axis in Dox-induced cardiomyopathy and suggested that targeting SNX3 provided a new effective therapeutic strategy for Dox-induced cardiomyopathy through TFRC-dependent ferroptosis.
Genome editing of PAR2 through targeted delivery of CRISPR-Cas9 system for alleviating acute lung inflammation via ERK/NLRP3/IL-1β and NO/iNOS signalling
Authors: Xin Zhuo, Yue Wu, Xiujuan Fu, Jianbin Li, Yuxin Xiang, Xiaoyu Liang, Canquan Mao, Yuhong Jiang
Journal: Acta Pharmaceutica Sinica B (2023)

Excessive and uncontrollable inflammatory responses in alveoli can dramatically exacerbate pulmonary disease progressions through vigorous cytokine releases, immune cell infiltration and protease-driven tissue damages. It is an urgent need to explore potential drug strategies for mitigating lung inflammation. Protease-activated receptor 2 (PAR2) as a vital molecular target principally participates in various inflammatory diseases via intracellular signal transduction. However, it has been rarely reported about the role of PAR2 in lung inflammation. This study firstly applied CRISPR-Cas9 system encoding Cas9 and sgRNA (pCas9-PAR2) for PAR2 knockout and fabricated an anionic human serum albumin-based nanoparticles to deliver pCas9-PAR2 with superior inflammation-targeting efficiency and stability (TAP/pCas9-PAR2). TAP/pCas9-PAR2 robustly facilitated pCas9-PAR2 to enter and transfect inflammatory cells, eliciting precise gene editing of PAR2 in vitro and in vivo. Importantly, PAR2 deficiency by TAP/pCas9-PAR2 effectively and safely promoted macrophage polarization, suppressed pro-inflammatory cytokine releases and alleviated acute lung inflammation, uncovering a novel value of PAR2. It is also revealed that PAR2-mediated pulmonary inflammation prevented by TAP/pCas9-PAR2 was mainly dependent on ERK-mediated NLRP3/IL-1β and NO/iNOS signalling. Therefore, this work indicated PAR2 as a novel target for lung inflammation and provided a potential nanodrug strategy for PAR2 deficiency in treating inflammatory diseases.
Corrigendum to “Does SARS-CoV-2 re-infection depend on virus variant?” [Clin Microbiol Infect 27 (9) (2021 Sep) 1374–1375]
Authors: Philippe Gautret, Linda Houhamdi, Nhu Ngoc Nguyen, Van Thuan Hoang, Audrey Giraud-Gatineau, Didier Raoult
Journal: Clinical Microbiology and Infection (2023)
Translating bacteriophage-derived depolymerases into antibacterial therapeutics: Challenges and prospects
Authors: Honglan Wang, Yannan Liu, Changqing Bai, Sharon Shui Yee Leung
Journal: Acta Pharmaceutica Sinica B (2023)

Predatory bacteriophages have evolved a vast array of depolymerases for bacteria capture and deprotection. These depolymerases are enzymes responsible for degrading diverse bacterial surface carbohydrates. They are exploited as antibiofilm agents and antimicrobial adjuvants while rarely inducing bacterial resistance, making them an invaluable asset in the era of antibiotic resistance. Numerous depolymerases have been investigated preclinically, with evidence indicating that depolymerases with appropriate dose regimens can safely and effectively combat different multidrug-resistant pathogens in animal infection models. Additionally, some formulation approaches have been developed for improved stability and activity of depolymerases. However, depolymerase formulation is limited to liquid dosage form and remains in its infancy, posing a significant hurdle to their clinical translation, compounded by challenges in their applicability and manufacturing. Future development must address these obstacles for clinical utility. Here, after unravelling the history, diversity, and therapeutic use of depolymerases, we summarized the preclinical efficacy and existing formulation findings of recombinant depolymerases. Finally, the challenges and perspectives of depolymerases as therapeutics for humans were assessed to provide insights for their further development.
Novel insights of EZH2-mediated epigenetic modifications in degenerative musculoskeletal diseases
Authors: Zetao Ma, Lei Chen, Yushun Wang, Sheng Zhang, Jianrui Zheng, Yuhong Luo, Chao Wang, Hui Zeng, Lixiang Xue, Zhen Tan, Deli Wang
Journal: Ageing Research Reviews (2023)
Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial
Authors: K. Jhaveri, L.D. Eli, H. Wildiers, S.A. Hurvitz, A. Guerrero-Zotano, N. Unni, A. Brufsky, H. Park, J. Waisman, E.S. Yang, I. Spanggaard, S. Reid, M.E. Burkard, S. Vinayak, A. Prat, M. Arnedos, F.-C. Bidard, S. Loi, J. Crown, M. Bhave, S.A. Piha-Paul, J.M. Suga, S. Chia, C. Saura, J.Á. Garcia-Saenz, V. Gambardella, M.J. de Miguel, E.N. Gal-Yam, A. Raphael, S.M. Stemmer, C. Ma, A.B. Hanker, D. Ye, J.W. Goldman, R. Bose, L. Peterson, J.S.K. Bell, A. Frazier, D. DiPrimeo, A. Wong, C.L. Arteaga, D.B. Solit
Journal: Annals of Oncology (2023)

HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T.
Identifying genetic regulatory variants that affect transcription factor activity
Authors: Xiaoting Li, Tuuli Lappalainen, Harmen J. Bussemaker
Journal: Cell Genomics (2023)

Genetic variants affecting gene expression levels in humans have been mapped in the Genotype-Tissue Expression (GTEx) project. Trans-acting variants impacting many genes simultaneously through a shared transcription factor (TF) are of particular interest. Here, we developed a generalized linear model (GLM) to estimate protein-level TF activity levels in an individual-specific manner from GTEx RNA sequencing (RNA-seq) profiles. It uses observed differential gene expression after TF perturbation as a predictor and, by analyzing differential expression within pairs of neighboring genes, controls for the confounding effect of variation in chromatin state along the genome. We inferred genotype-specific activities for 55 TFs across 49 tissues. Subsequently performing genome-wide association analysis on this virtual trait revealed TF activity quantitative trait loci (aQTLs) that, as a set, are enriched for functional features. Altogether, the set of tools we introduce here highlights the potential of genetic association studies for cellular endophenotypes based on a network-based multi-omics approach. The transparent peer review record is available.
Aligning NIH’s existing data use restrictions to the GA4GH DUO standard
Authors: Jonathan Lawson, Elena M. Ghanaim, Jinyoung Baek, Harin Lee, Heidi L. Rehm
Journal: Cell Genomics (2023)

It is widely accepted that large-scale genomic data (e.g., whole-genome sequencing, whole-exome sequencing, and genome-wide association study data) be shared through a controlled-access mechanism. This protects the privacy of research participants and ensures downstream uses of data align with participants' informed consent regarding future sharing of their data. In 2019, GA4GH approved the Data Use Ontology (DUO) standard to define data use terms with machine-readable representations to represent how a dataset can be used. We endeavored to determine the parity of existing data use restrictions ("Data Use Limitations" [DULs]) for datasets registered in the National Institutes of Health database for Genotypes and Phenotypes (dbGaP) with the DUO standard. We found substantial (93%) parity between the dbGaP DULs (n = 3,575) and DUO. This study demonstrates the comprehensiveness of the DUO standard and encourages data stewards to standardize data use restrictions in machine-readable formats to facilitate data sharing.
A regulatory circuit controlled by extranuclear and nuclear retinoic acid receptor α determines T cell activation and function
Authors: Alexandre Larange, Ikuo Takazawa, Kiyokazu Kakugawa, Nicolas Thiault, SooMun Ngoi, Meagan E. Olive, Hitoshi Iwaya, Laetitia Seguin, Ildefonso Vicente-Suarez, Stephane Becart, Greet Verstichel, Ann Balancio, Amnon Altman, John T. Chang, Ichiro Taniuchi, Bjorn Lillemeier, Mitchell Kronenberg, Samuel A. Myers, Hilde Cheroutre
Journal: Immunity (2023)
Interaction of an α-synuclein epitope with HLA-DRB1∗15:01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease
Authors: Francesca Garretti, Connor Monahan, Nicholas Sloan, Jamie Bergen, Sanjid Shahriar, Seon Woo Kim, Alessandro Sette, Tyler Cutforth, Ellen Kanter, Dritan Agalliu, David Sulzer
Journal: Neuron (2023)

Enteric symptoms are hallmarks of prodromal Parkinson's disease (PD) that appear decades before the onset of motor symptoms and diagnosis. PD patients possess circulating T cells that recognize specific α-synuclein (α-syn)-derived epitopes. One epitope, α-syn32-46, binds with strong affinity to the HLA-DRB1∗15:01 allele implicated in autoimmune diseases. We report that α-syn32-46 immunization in a mouse expressing human HLA-DRB1∗15:01 triggers intestinal inflammation, leading to loss of enteric neurons, damaged enteric dopaminergic neurons, constipation, and weight loss. α-Syn32-46 immunization activates innate and adaptive immune gene signatures in the gut and induces changes in the CD4+ TH1/TH17 transcriptome that resemble tissue-resident memory (TRM) cells found in mucosal barriers during inflammation. Depletion of CD4+, but not CD8+, T cells partially rescues enteric neurodegeneration. Therefore, interaction of α-syn32-46 and HLA-DRB1∗15:0 is critical for gut inflammation and CD4+ T cell-mediated loss of enteric neurons in humanized mice, suggesting mechanisms that may underlie prodromal enteric PD.
Polygenic regression uncovers trait-relevant cellular contexts through pathway activation transformation of single-cell RNA sequencing data
Authors: Yunlong Ma, Chunyu Deng, Yijun Zhou, Yaru Zhang, Fei Qiu, Dingping Jiang, Gongwei Zheng, Jingjing Li, Jianwei Shuai, Yan Zhang, Jian Yang, Jianzhong Su
Journal: Cell Genomics (2023)

Advances in single-cell RNA sequencing (scRNA-seq) techniques have accelerated functional interpretation of disease-associated variants discovered from genome-wide association studies (GWASs). However, identification of trait-relevant cell populations is often impeded by inherent technical noise and high sparsity in scRNA-seq data. Here, we developed scPagwas, a computational approach that uncovers trait-relevant cellular context by integrating pathway activation transformation of scRNA-seq data and GWAS summary statistics. scPagwas effectively prioritizes trait-relevant genes, which facilitates identification of trait-relevant cell types/populations with high accuracy in extensive simulated and real datasets. Cellular-level association results identified a novel subpopulation of naive CD8+ T cells related to COVID-19 severity and oligodendrocyte progenitor cell and microglia subsets with critical pathways by which genetic variants influence Alzheimer's disease. Overall, our approach provides new insights for the discovery of trait-relevant cell types and improves the mechanistic understanding of disease variants from a pathway perspective.
Metabolic classification suggests the GLUT1/ALDOB/G6PD axis as a therapeutic target in chemotherapy-resistant pancreatic cancer
Authors: Yunguang Li, Shijie Tang, Xiaohan Shi, Jingwen Lv, Xueyuan Wu, Yehan Zhang, Huan Wang, Juan He, Yiqin Zhu, Yi Ju, Yajuan Zhang, Shiwei Guo, Weiwei Yang, Huiyong Yin, Luonan Chen, Dong Gao, Gang Jin
Journal: Cell Reports Medicine (2023)

Metabolic reprogramming is known as an emerging mechanism of chemotherapy resistance, but the metabolic signatures of pancreatic ductal adenocarcinomas (PDACs) remain unclear. Here, we characterize the metabolomic profile of PDAC organoids and classify them into glucomet-PDAC (high glucose metabolism levels) and lipomet-PDAC (high lipid metabolism levels). Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression. Pharmacological inhibition of GLUT1 or G6PD enhances the chemotherapy response of glucomet-PDAC. Our findings uncover potential metabolic heterogeneity related to differences in chemotherapy sensitivity in PDAC and develop a promising pharmacological strategy for patients with chemotherapy-resistant glucomet-PDAC through the combination of chemotherapy and GLUT1/ALDOB/G6PD axis inhibitors.
Table of Contents
Authors: Yun Xia, Letizia De Chiara, Iain Drummond, Tilman Drueke, Ziad Massy, Jason Smith, Maria Luisa, S Sequeira-Lopez, R Gomez, Yu Kurata, Masaomi Nangaku, Yasuna Nakamura, Tsuyoshi Inoue, Michael Mengel, Mark Haas, P Coates, Germaine Wong, Rajnish Mehrotra, Sara Davison, Ken Farrington, Jennifer Flythe, Marjorie Foo, Magdalena Madero, Rachael Morton, Yusuke Tsukamoto, Mark Unruh, Michael Cheung, Michel Jadoul, Wolfgang Winkelmayer, Edwina Brown
Journal: Kidney International (2023)
Women in Academic Medicine
Authors: Wendy Levinson, Susan W. Tolle, Charles Lewis
Journal: New England Journal of Medicine (1989)

Abstract We conducted a national survey to explore how women in academic medicine balance career and family responsibilities. A questionnaire was mailed to all women 50 years of age and under who held full-time appointments in departments of medicine (n = 862), as listed in the faculty roster of the Association of American Medical Colleges. The survey included questions about childbearing and child rearing, attitudes about personal and professional issues, and role models. Of the 694 questionnaires that were delivered, over 80 percent were completed (n = 558). The mean age of the respondents was 38.1 years, and 63 percent had children. The 350 mothers had a mean of 1.9 children; only 3 had 4 or more children. Approximately half the respondents with children had their first child after completing medical training (mean age, 30.6 years), and they were absent from work for a median of 6 weeks post partum; 72 percent took no time off before labor and delivery, and 83 percent were back at work within 12 weeks. The majority were satisfied with their decision to have children and with their careers, despite the fact that 78 percent believed that their career progress had been slowed or markedly slowed by their having had children. We conclude that it is possible for women to combine motherhood with a fulfilling career in academic medicine, but it is difficult, and most such women believe that motherhood slows the progress of their careers. (N Engl J Med 1989;321:1511–7.)